Of the interleukin-17 cytokine family, the functions of IL-17B, IL-17C, and IL-17D remain largely elusive. Iwakura, et al., Immunity (2011) 34(2):149-62. Little is known about the role of IL-17 in de novo carcinogenesis. The role of T helper type 17 cells, which produce interleukin-17A (IL-17A) in particular, has been controversial. Wang and colleagues have found that IL-17A supports cancer-associated inflammation in the tumor microenvironment, enhancing tumor development in carcinogen-induced skin cancer. Wang, Cancer Res. (2010) 70(24):10112-20. In another study, Zhu, et al., concludes that IL-17A expression by breast-cancer-associated macrophages promotes invasiveness of breast cancer cell lines. Zhu, et al., Breast Cancer Research (2008) 10(6):R95. There are no published studies on the role of IL-17D in cancer prevention or therapy.
The process of cancer immunoediting generates a repertoire of cancer cells that can persist in immune competent hosts (Shankaran, V. et al. Nature (2001) 410:1107-1111; Dunn, et al., Nature Immunol. (2002) 3:991-998; Koebel, et al., Nature (2007) 450, 903-907; Vesely, et al., Annu. Rev. Immunol. (2011) 29:235-271; Schreiber, et al., Science (2011) 331:1565-1570). In its most complex form, cancer immunoediting involves the initial elimination of immunogenic tumor cells, followed by a state of equilibrium, whereby tumor cells and immune cells co-exist without apparent growth of the tumor mass, and ending in escape, whereby immune evasive cancers arise. When cancer immunoediting is impaired in immune deficient hosts, the resultant tumor cell repertoire is “unedited” and contains highly immunogenic cancer cells. For example, 3′methylcholanthrene (MCA)-induced sarcomas that develop in WT mice are edited and poorly immunogenic whereas similar sarcomas that develop in immune deficient RAG2−/− mice are unedited and highly immunogenic (Shankaran et al., Nature 2001, supra). In these studies, the immunogenicity of the tumor cell lines was determined by transplanting them into WT mice, leading to the definition of “progressor” tumor cell lines as edited cells that evade the immune system and “regressor” cell lines as unedited cell lines that cannot grow when transplanted in WT mice but can grow in immune deficient mice. Thus, progressor cells represent the typical cancer cell that arises in human cancer patients with an intact immune system, whereas regressor cells (often derived from immune deficient mice) are unique cells that can activate the immune system to induce tumor rejection. Indeed, immune cells can efficiently infiltrate, recognize, become activated, and eliminate regressor but not progressor tumor cells (Bui, et al., Cancer Res (2006) 66:7301-7309; Koebel, et al., Nature (2007) 450:903-907; Vesely, et al., Annu. Rev. Immunol. (2011) 29:235-271; Schreiber, et al., Science (2011) supra) but it is not known how tumor-expressed genes can influence each of these steps. In particular, the molecular differences between edited and unedited tumor cells are poorly defined.